Cyclopropane derivatives such as 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one are known to have a potent antiviral activity.
A first method for the preparation of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one is disclosed in patent EP0502690. The reaction sequence disclosed in these documents involves the preparation of ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate from R-(−)-epichlorohydrin and diethyl malonate with high optical purity. Subsequent transformation to (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropylmethyl p-toluenesulfonate requires 8 further steps, including several protection and deprotection steps. The (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropylmethyl p-toluenesulfonate is then coupled with 2-amino-6-benzyloxy-purine. Finally, removal of all hydroxyl protecting groups results in the formation of the desired product. In one of the steps, a dimethyl ketal function is used as dial protecting group while transforming the ester function to hydroxyl. However, due to its low stability, this protecting group has to be replaced for further transformation of the hydroxyl to a leaving group.
In the synthesis of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one analogues described in patent EP0649840, it is further demonstrated that the use of the more robust diphenyl ketal function eliminates the need of the replacement of the diol protecting group during the synthesis. However, setting up that protecting group requires the use of highly toxic 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and the potentially explosive diphenyldiazomethane.
Another method for the preparation of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one is disclosed in patent EP0675123. The reaction sequence disclosed in these documents is similar to the method described hereinabove. Specifically, ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate is prepared from R-(−)-epichlorohydrin and diethyl malonate with high optical purity. The ester function is then selectively reduced to hydroxyl, while the lactone moiety is opened and reclosed. Then, the hydroxyl group is transformed further to a leaving group and the compound
is coupled with 2-amino-6-chloropurine. Finally, hydrolysis of the base moiety into guanine and subsequent reduction of the lactone ring to diol results in the formation of the desired product.
The formal synthesis of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one, involving the intramolecular cyclopropanation of a D-ribose derived unsaturated diazo compound as key step, is described by Gallos et al. in Tetr. Lett. 2001, 42, 7489.
The above described methods suffer from certain disadvantages: the synthesis routes involve several time-consuming protection and deprotection steps, require the use of hazardous products, and/or involve the use of intermediates with low stability. Accordingly, there is a need for synthesis methods for cyclopropane derivatives such as 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-purin-6-one, which mitigate at least one of the problems stated above.